MISCELLANEA ON ENCEPHALOPATHIES – A SECOND LOOK Edited by Radu Tanasescu MISCELLANEA ON ENCEPHALOPATHIES – A SECOND LOOK Edited by Radu Tanasescu Miscellanea on Encephalopathies – A Second Look Edited by Radu Tanasescu Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. 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Publishing Process Manager Molly Kaliman Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published April, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechopen.com Miscellanea on Encephalopathies – A Second Look, Edited by Radu Tanasescu p. cm. ISBN 978-953-51-0558-9 Contents Chapter 1 Minimal Hepatic Encephalopathy (MHE) 1 Daniela Benedeto-Stojanov and Dragan Stojanov Chapter 2 Uremic Encephalopathy 23 Annemie Van Dijck, Wendy Van Daele and Peter Paul De Deyn Chapter 3 Drug-Induced Encephalopathy 39 Niels Hansen Chapter 4 Sonographic Changes in Hypoxic-Ischaemic Encephalopathy 61 Pilvi Ilves Chapter 5 Neoplasm Related Encephalopathies 91 Lore Lapeire, Anne Sieben, Patrick Santens and Simon Van Belle Chapter 6 Hepatic Encephalopathy 121 Jeffrey E. Juneau and Brendan M. McGuire Chapter 7 Hypoxic Encephalopathy 149 Mireia Moragas Garrido and Jordi Gascón Bayarri Chapter 8 Encephalopathy Associated with Psychotropic Drug Therapy 167 Yuji Odagaki Chapter 9 The Use of Microdialysis in the Study of Encephalopathies 199 Liliana Carmona-Aparicio, Liliana Rivera-Espinosa and Hugo Juárez-Olguín Chapter 10 Portal-Systemic Encephalopathy in Emergency Treatment of Cirrhosis and Bleeding Esophageal Varices 225 Marshall J. Orloff VI Contents Chapter 11 Future Perspectives for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy 243 Pedro M. Pimentel-Coelho, Marcelo F. Santiago and Rosalia Mendez-Otero Chapter 12 Molecular Defects of Vitamin B 6 Metabolism Associated with Neonatal Epileptic Encephalopathy 267 Mohini S. Ghatge, Martino L. Di Salvo, Roberto Contestabile, Dorothy N. Eseonu, Sayali Karve, Verne Schirch and Martin K. Safo Chapter 13 Disaccharides in the Treatment of Hepatic Encephalopathy in Patients with Cirrhosis 291 Praveen Sharma Chapter 14 Dopaminergic Dysfunction in Experimental Hepatic Encephalopathy 309 Isabel Suárez, Guillermo Bodega and Benjamín Fernández Chapter 15 Wernicke’s Encephalopathy 327 Radu Tanasescu, Laura Dumitrescu, Carmen Dragos, Dimela Luca, Alexandra Oprisan, Catalina Coclitu, Oana Simionescu, Lorena Cojocaru, Marius Stan, Andreea Carasca, Andreea Gitman, Adela Chiru and Marina Ticmeanu Chapter 16 L-carnitine in Hyperammonemia and Hepatic Encephalopathy 365 Jane Missler and Claudia Zwingmann 1 Minimal Hepatic Encephalopathy (MHE) Daniela Benedeto-Stojanov and Dragan Stojanov Faculty of Medicine, University of Nis Serbia 1. Introduction Hepatic encephalopathy (HE) reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease. Classification of hepatic encephalopathy is based on the clinical setting in which symptoms occur (Table 1). 1 The encephalopathy of acute liver failure shares clinical characteristics with that of cirrhosis, but also exhibits unique features. In cirrhosis, three major syndromes can be present: 1. Episodic (precipitant-induced) encephalopathy, commonly seen in the hospital setting, where a superimposed event is a key factor. 2. Persistent (chronic) encephalopathy, seen with extensive portal–systemic shunts and after portocaval shunt surgery or placement of transjugular intrahepatic portosystemic shunt (TIPS). 3. Minimal (subclinical) encephalopathy reflects alterations in cognitive function in patients who clinically exhibit a normal mental state. Hepatic failure Extrahepatic portal-systemic shunting Special features Acute liver failure Maximal Absent Development of brain oedema and intracranial hypertension Cirrhosis Low-grade cerebral oedema without overt signs of intracranial hypertension Episodic encephalopathy Variable Variable Precipitant induced Persistent encephalopathy Variable Genarally large Most often seen after portocaval surgery or TIPS Minimal encephalopathy Variable Variable Requires neuropsychological/ neurophysiological testing TIPS, transjugular intrahepatic portosystemic shunt. Table 1. Classification of hepatic encephalopathy. Miscellanea on Encephalopathies – A Second Look 2 Minimal hepatic encephalopathy (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits, and impairs health-related quality of life (HRQOL). 2 Cirrhotic patients with MHE have a normal neurological and mental status by the standards of clinical examination, yet demonstrate quantifiable neuropsychological defects. 3 The term MHE refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy. 4 MHE has been described previously using several different names, such as, early, low- grade, latent or subclinical HE to identify patients with subtle cognitive function abnormalities. These subtle neurocognitive abnormalities primarily affect attention, speed of information processing, and motor abilities and coordination that are not recognizable on standard neurological examination. These neurocognitive abnormalities are independent of sleep dysfunction or problems with overall intelligence. 5-8 It has been well-described that MHE has a subtle but negative impact on a patient’s spatial skills, motor skills, the ability to perform complex tasks such as driving, and even quality of life. 3-5 MHE predicts the development of overt HE and is associated with poor survival 2 . Its negative impact on daily living, among other reasons, has led some authors to suggest that the failure to diagnose this condition could be classified as a medical error. 9,10 2. Epidemiology There are no accurate data on the incidence of HE. HE is classified as: overt hepatic encephalopathy (OHE) and MHE. OHE occurs in 30% to 45% of cirrhotic patients 11 and in 10% to 50% of patients with TIPS 12 and can be clinically diagnosed. The true prevalence of MHE in patients with portal hypertension is inknown. MHE has been diagnosed in patients with liver cirrhosis and in patients with noncirrhotic portal hypertension. The prevalence of MHE has been reported in as many as 20%−84% of cirrhotics, depending on which methods or tools are used and fixed diagnostic cut-offs. 2,3 Large variations in the prevalence of MHE are related to prior episode of OHE, severity of liver disease, age, preasence of esophageal varices, and surgical porto-systemic shunts. Patients who develop MHE are older, more often have alcohol as etiology of cirrhosis, have history of overt HE in the past, have more severe liver disease, and more often have esophagogastric varices. 2,13 3. Pathogenesis Despite much scientific research, the exact pathophysiological mechanisms leading to HE are not clearly understood. The most widely accepted theory of the pathogenesis of HE is that nitrogenous substances derived from the gut adversely affect the cerebral function. Minimal Hepatic Encephalopathy (MHE) 3 3.1 Ammonia There are various explanations why liver dysfunction or portosystemic shunting might lead to encephalopathy. In healthy subjects, intestinal neurotoxins, such as ammonia, manganase and the benzodiazepine-GABA system generated by gut bacteria from food, are transported by the portal vein to the liver, where 80–90% is metabolized and/or excreted immediately. In all subtypes of hepatic encephalopathy this process is impaired, either because the hepatocytes are incapable of metabolizing the neurotoxins or because portal venous blood bypasses the liver through collateral circulation or a medically constructed shunt. Neurotoxins accumulate in the systemic circulation. Ammonia plays a key role in the pathogenesis of HE. The small molecules of ammonia cross the blood-brain barrier and are absorbed and metabolized by astrocytes, population of cells in the brain that constitutes 30% of the cerebral cortex. Alzheimer type II astrocytes are the only cells containing glutamine synthetase that metabolize ammonia. It is hypothesed that glutamine synthesis within the astrocytes causes brain swelling. 14,15 Astrocytes also provide physical and nutritional support for neurons, maintain the integrity of the blood–brain barrier and regulate cerebral blood flow. 16 Ammonia also modulates glutamate neurotransmission and induces neurosteroid production in neurons, leading to a positive modulatory effect on the gamma- aminobutyric acid-A receptor. 17 The precise molecular mechanism(s) responsible for neurological alteration in HE are not known. HE is associated with alterations in the expression of astrocytic and neuronal genes that code for various proteins that play a critical role in central nervous system function including maintenance of cell volume and neurotransmission. 14 The pathogenesis of MHE is similar to that of HE. 18-22 An increase in brain glutamine and brain water is pathophysiological change associated with deterioration in neuropsychological performance. Alterations in cerebral blood flow and glucose metabolism induced by ammonia are associated with a significant decrease of glucose utilization by various cortical regions that are involved in cognitive functions. 21 The cerebral metabolic rate for ammonia and the permeability-surface area product for ammonia are significantly higher in patients with MHE. 21 The increased permeability-surface area product of the blood–brain barrier permits ammonia to diffuse across the blood–brain barrier into the brain more freely than normal. This may cause ammonia-induced encephalopathy even though arterial ammonia levels are normal or near normal. Cognitive deficits observed in patients with noncirrhotic portal hypertension have also been linked to ammonia. 18 Patients with noncirrhotic portal hypertension, such as extrahepatic portal venous obstruction, exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and magnetic resonance (MR) imaging and spectroscopy similar to those described in HE associated with cirrhosis. 22 Other waste products implicated in hepatic encephalopathy include mercaptans (substances containing a thiol group), short-chain fatty acids and phenol.23 3.2 Serotonin Serotonin, a neurotransmitter with widespread distribution in the CNS, is important for the regulation of sleep, circadian rhythmicity and locomotion. Changes in the synthesis, metabolism, storage and release of neuronal serotonin in HE suggest a serotonergic synaptic [...]... 2007;25:1 1–1 6 18 Miscellanea on Encephalopathies – A Second Look [8] Kharbanda PS, Saraswat VA, Dhiman RK Minimal hepatic encephalopathy: diagnosis by neurophchological and neurophysiological methods Indian J Gastroenterol 2003; 22: 53 7–5 41 [9] Ortiz M, Jacas C, Cordoba J Minimal hepatic encephalopathy: diagnosis, clinical signifi cance and recommendations J Hepatol 2005;42: 4 5–5 3 [10] Lockwood AH “What’s...4 Miscellanea on Encephalopathies – A Second Look deficit Serotonin metabolism is exquisitely and selectively sensitive to the degree of portosystemic shunting and hyperammonaemia, suggesting a role for serotonin in early neuropsychiatric symptoms of HE.24 3.3 Branched-chain amino acids (BCAA) and false neurotransmitters An imbalans between aromatic aminoacids (AAA) (phenylalanine, tryptophan and... frontal rhythmic theta activity and paroxysmal, bilateral, high voltage delta waves are also frequent Sometimes bilateral spike-waves complexes or triphasic waves in the frontal regions are found (Fig 1) Convulsions are often a late stage manifestation of chronic renal failure Seizures are usually generalized tonic-clonic convulsions Nevertheless, focal motor seizures are not uncommon Epilepsia partialis... battery examines many of the abnormalities seen in patients with MHE, including motor speed and accuracy, visuo-spatial orientation, visual perception, visual construction, attention, concentration, and, to a lesser extent, memory PHES has a prognostic value for the occurrence of overt HE and mortality in cirrhotic patients.74,75 12 Miscellanea on Encephalopathies – A Second Look The RBANS contains measures... tryptophan and tyrosine) and branched-chain amino acids (BCAA)(leucine, isoleucine and valine) has been described in patients with severe liver dysfunction AAA and BCAA share a common transport mechanism into the CNS AS a consequence of increased concentration of AAA, neuronal levels may be raised leading to the production of false neurotransmitters (octopamide and phenylethanolamide)25 with subsequent... minimal hepatic encephalopathy Hepatology 2008; 47: 59 6–6 04 [53] Venktaramarao SH, Mittal, Prabhakar S, Dhiman RK Brain perfusion single photon emission computed tomography (SPECT) abnormalities in patients with minimal hepatic encephalopathy (abstract) J Gastroenterol Hepatol 2008; 23 : A6 2 [54] Grover VP, Dresner MA, Forton DM, et al Current and future applications of magnetic resonance imaging and... spectroscopy alterations and cerebral ammonia and glucose metabolism in cirrhotic patients with and without hepatic encephalopathy Gut 2007; 56: 173 6–4 2 [96] Lodi R, Tonon C, Stracciari A et al Diffusion MRI shows increased water apparent diffusion coefficient in the brains of cirrhotics Neurology 2004; 62: 76 2–6 [97] Kale RA, Gupta RK, Saraswat VA et al Demonstration of interstitial cerebral edema with... the patients 4 Clinical characteristics OHE is traditionally classified into four grades according to the West Haven criteria (Table 2).6 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Lack of detectable changes in personality or behavior No asterixis Trivial lack of awareness Euphoria or anxiety Shortened attention span Impaired performance of addition Asterixis may be present Lethargy or apathy Minimal disorientation... 62 2–3 0 20 Miscellanea on Encephalopathies – A Second Look [46] Watanabe A, Tuchida T, Yata Y, Kuwabara Y Evaluation of neuropsychological function in patients with liver cirrhosis with special reference to their driving ability Metab Brain Dis 1995;10: 23 9–4 8 [47] Wein C, Koch H, Popp B, Oehler G, Schauder P Minimal hepatic encephalopathy impairs fitness to drive Hepatology 2004; 39:73 9–4 5 [48] Marotolli... compared with healthy controls Affects an estimated 60% (50% to 80%)* of patients with cirrhosis Cerebral dysfunction has a major impact on patients’ daily living  The presence of a disease that can cause MHE, such as, cirrhosis and/or the presence of a portalsystemic shunt  normal mental status on clinical examination  demonstration of abnormalities of cognition and/or neurophysiological variables . MISCELLANEA ON ENCEPHALOPATHIES – A SECOND LOOK Edited by Radu Tanasescu MISCELLANEA ON ENCEPHALOPATHIES – A SECOND LOOK Edited by Radu Tanasescu Miscellanea. Encephalopathy 327 Radu Tanasescu, Laura Dumitrescu, Carmen Dragos, Dimela Luca, Alexandra Oprisan, Catalina Coclitu, Oana Simionescu, Lorena Cojocaru, Marius Stan, Andreea Carasca, Andreea Gitman,. dysfunction. AAA and BCAA share a common transport mechanism into the CNS. AS a consequence of increased concentration of AAA, neuronal levels may be raised leading to the production of false neurotransmitters